Are There Definitive Tests For Histamine Intolerance?

Histamine intolerance is both difficult for patients to bare and also difficult for clinicians to diagnose. The symptoms of histamine intolerance can be nebulous. So it's difficult for physicians to identify the condition.

In this post, I'll discuss histamine intolerance tests, i.e., how you can determine whether or not you're histamine intolerant.

Before we dive in, here's a quick overview of the roles histamine plays in the body. Histamine:

Acts as a wake-promoting neurotransmitter in the brain. For example, antihistamines make you drowsy and histaminergic drugs like modafinil wake you up.

Helps white blood cells fight infection and participates in the local immune response.

Is a key mediator of allergic and nonallergic diseases. Histamine plays a role in allergic rhinitis, urticaria, and anaphylaxis and in bronchial asthma.

Controversy

There's some controversy about whether ingested histamine plays an important role in histamine intolerance.

Some smart people seem[^1] to think that histamine intolerance falls under the purview of pseudoscience[^2]:

Since there is no objective investigation to prove histamine intolerance, the diagnosis is based on symptoms. On the basis of literature, better clinical studies are needed. Because the phenomenon remains unclear, use of the terms histamine intolerance and pseudoallergens is not recommended.

But the prevailing view seems to be that histamine intolerance is real, and that ingested histamine provokes reactions in histamine intolerant individuals. One study showed that priming healthy volunteers with histamine, and then feeding them histamine-rich food like wine and cheese, resulted in serious adverse reactions.

Role of Diamine Oxidase

The role of DAO in histamine intolerance has also recently been called into question. Schwelberger recently published the following statement:

Evaluation of more than 200 scientific journal articles and over 30 patient oriented websites dealing with this disease concept Diamine oxidase (DAO) revealed that a lot more is being alleged and stated than is actually substantiated by scientific evidence.

Moreover, an experiment measuring the histamine degrading enzymatic activity of human skin homogenates suggests that the main histamine degrading enzyme is N-methyl-transferase, not DAO. Let's set this finding aside for a moment.

Testing For Histamine Intolerance

Unfortunately, there's no routine test or validated questionnaire for histamine intolerance. Clinicians diagnose histamine intolerance based on case history.

If you suspect you're intolerant to histamine, your best bet is talking to a doctor. They might suggest that you eliminate histamine-rich foods from your diet and see if your symptoms resolve. If you start feeling better, you can reintroduce foods histamine-containing foods and see if they provoke a reaction.

Though no diagnostic tests for histamine intolerance are widely available, a number of tests have been proposed in the medical literature. In the next few sections, we'll discuss these tests.

Oral Histamine Provocation

Historically, oral provocation with aqueous (liquid) histamine has been used. In histamine intolerant folks, you expect aqueous histamine to provoke an adverse reaction.

This approach has been criticized because it's difficult to standardize. Even in patients with overt histamine intolerance oral provocation was positive in only 50% of those tested [^6].

Moreover, Komericki and colleagues recently published a study on the unreliability of blinded oral histamine provocation to confirm histamine intolerance [^7]. However, the authors did report:
The intake of DAO demonstrated a statistically significant reduction of histamine-associated symptoms compared to placebo (P = 0.014).

In other words, ingested diamine oxidase reduced the symptoms of histamine intolerance! I find this result most striking of all because most ingested enzymes are hydrolyzed (degraded) in the gastrointestinal tract by peptidases. So it's surprising that ingested diamine oxidase made it into the body intact.

Serum Diamine Oxidase Activity

Assuming that diamine oxidase plays a role in histamine intolerance, we might expect patients with histamine intolerance to have reduced DAO activity.

One study[^3] suggests that serum diamine oxidase activity can be used as a diagnostic test for histamine intolerance. The authors enrolled over 300 participants with suspected histamine intolerance. They noted that DAO activity in this cohort was significantly lower than in healthy controls.

The authors next identified 54 study participants with severely reduced diamine oxidase activity. "Severely reduced DAO activity" was defined as less than 40 HDU/mL. This group went on a histamine-free diet for 6-12 months. After adopting a histamine-free diet, the main symptoms of histamine intolerance resolved.

More recently, the diamine oxidase/histamine link has been called into question[^5].

Recently, a commercial radioimmunoassay for determination of DAO activity has been launched. To evaluate the clinical impact of this assay for the diagnosis of histamine intolerance, we performed a prospective, multicentre study in 207 adult patients. In 77 patients, a diagnosis of histamine intolerance was made based on clinical criteria, in 67 a diagnosis "in question", and 61 healthy patients without anamnestic evidence for histamine intolerance served as a control. Interestingly, no correlation between diamine oxidase serum levels and clinical status could be found in any of the 3 groups. We, therefore, recommend further investigations, before determination of DAO serum activity should be used as a screening tool for the diagnosis of histamine intolerance.

Based on the unreliability of the diamine oxidase/histamine intolerance link, Kofler et al. went on to develop a skin-prick diagnostic test.

The Histamine Intolerance Skin-Prick Test

Kofler and colleagues sought to develop a prick-test for the diagnosis of histamine intolerance.

They state their approach as follows:

Prick-testing with 1% histamine solution and wheal size-measurement to assess the relation between the wheal in prick-test, read after 20 to 50 minutes, as sign of slowed histamine degradation as well as history and symptoms of histamine intolerance.

In other words, the authors exposed participants to histamine (1% histamine solution) and then assayed the rate of histamine degradation after exposure. You could identify histamine intolerance patients because with this test because they would be expected to exhibit slowed histamine clearance.